Method of inhibiting herpetic lesions by the use of platinum coordination compounds

ABSTRACT

A method is provided for inhibiting herpetic lesions associated with herpes virus infection in warm blooded animals comprising topically administering to any such warm blooded animal a lesion-inhibiting amount of antiherpes platinum coordination compound contained in a pharmaceutical composition in topical dosage form.

REFERENCE TO A RELATED APPLICATION

This application is a division of application Ser. No. 505,216, filedJune 17, 1983, issued Feb. 18, 1986, as U.S. Pat. No. 4,571,335.

1. Technical Field

This invention is directed to pharmaceutical means in composition ordosage form containing an antiviral component comprising a herpes virusinhibiting amount of platinum coordination compound and to a method ofinhibiting lesions associated with herpes infection in warm bloodedanimals using the composition or dosage form.

2. Background of the Invention

A wide variety of methods have been used over the years for thesymptomatic relief of pain and remission of lesions such as feverblisters or cold sores associated with herpes infection attributed toherpes virus, particularly herpes simplex virus, type 1 or type 2. Oneway of treating the lesions presented by herpes virus infection callsfor topical application on the lesion of a pharmaceutical formulationthat contains idoxuridine as the active ingredient. Idoxuridine is anantimetabolite that interferes with DNA synthesis. It is poorlywater-soluble and is used as a dilute solution in a suitable non-aqueousvehicle or solvent such as dimethylsulfoxide. Another way of treatingherpes virus infection calls for topical application, on the lesion, ofa formulation containing the antimetabolite vidarabine. However,attempts to eradicate genital or oral herpes virus infection by localapplication of vidarabine have failed to show substantial benefit.

It is known from U.S. Pat. No. 4,305,390 that cis-platinumdiaminodichloride may be used as an activator in the presence of light,oxygen and an electric field to inactivate herpes simplex virus type 1.

It is also known from U.S. Pat. No. 4,053,587 to treat viral infectionby parenteral administration of a composition in dosage form containinga platinum coordination compound as an active antiviral component. Ithas also been proposed in U. S. Pat. No. 4,255,417, concerning skinblemishes such as warts and moles, to apply topically a platinumcompound to achieve disappearance of the treated blemish. However,treatment of herpetic lesions by the topical route using a platinumcoordination compound in dosage form is not known.

In view of the limitations of current therapy for treatment of lesionsassociated with herpes virus infection, a need for additionaltherapeutic methods exists.

SUMMARY AND DETAILED DESCRIPTION

The present invention is based on the unexpected finding that platinumcoordination compounds when topically applied in a suitable dosage formpossess useful pharmacological properties for controlling and inhibitingherpetic skin lesions.

The invention in one aspect relates to a method of inhibiting herpeticlesions in warm blooded animals comprising:

applying to the surface of the lesions of any such warm blooded animal aherpes virus inhibiting amount of platinum coordination compoundcontained in a pharmaceutical composition in topical dosage form. Theplatinum coordination compound content, for purposes of the invention,can be that of a single compound or two or more compounds selected fromthe group of compounds comprising sub-groups (a) and (b), as follows:

(a) cisplatin, cis-dichlorodihydroxy bis-isopropylamine platinum (IV),diammine-1,2-cyclobutanedicarboxylatoplatinum (II),1,2-diaminocyclohexane malonatoplatinum (II), 1,2-diaminocyclohexanesulphatoplatinum (II), 1,2-diaminocyclohexane hydroxma,lonatoplatinum(II), ethylenediamine malonatoplatinum (II), and diammineethylmalonatoplatinum (II), and

(b) cisplatin derivatives having the formula

    cis-[Pt(NH.sub.3).sub.2 P.sub.x Cl.sub.y ]Cl.sub.z

where x is one or two, y and z being one when x is one and being zeroand .two when x is two, and P is an antiviral compound of the groupconsisting of ara-A, acyclovir, ara-ADA, FIAC, FMAU, cyclaradine, andDHPG, also known as 9-β-D-arabinofuranosyladenine (ara-A or Vira-A),9-[(2-hydroxyethoxy)methyl]guanine (acyclovir or Zovirax), the2',3'-diacetate of ara-A (ara-ADA), 2'-fluoro-5-iodoarabinosylcytosine(FIAC), 2'-fluoro-5- methyl-arabinosyluracil (FMAU), the carbocyclicanalog of ara-A (cyclaradine), and9-(1,3-dihydroxy)-2propoxymethyl)guanine (DHPG).

The invention in a preferred aspect relates to the method, as described,wherein the content of platinum coordination compound in the compositionis solely that of cisplatin.

The invention in another preferred aspect relates to the method, asdescribed, wherein the content of platinum coordination compound in thecomposition is that of a compound or compounds of sub-group (a). Thestructures and aqueous solubility of the latter compounds are tabulatedas follows:

    __________________________________________________________________________                                       Aqueous Solubility                         Structural Formula  Compound       (mg/ml)                                    __________________________________________________________________________     ##STR1##           cisplatin      2.53                                        ##STR2##           cis-dichlorodihydroxy bis isopropylamine platinum                             (IV)           20                                          ##STR3##           diammine-1,1-cyclobutane dicarboxylatoplatinum                                               17.8                                        ##STR4##           1,2-diaminocyclohexane malonato platinum                                                     0.2)                                        ##STR5##           1,2-diaminocyclohexane sulphatoplatinum                                                      12I)                                        ##STR6##           1,2-diaminocyclohexane hydroxymalonatoplatinum                                               0.20                                        ##STR7##           ethylenediamine malonato platinum (II)                                                       6                                           ##STR8##           diammine ethylmalonato platinum (II)                                                         57                                         __________________________________________________________________________

The invention in another preferred aspect relates to the method, asdescribed, wherein the content of platinum coordination compound in thecomposition is that of a compound or compounds of sub-group (b).

Pharmaceutical compositions contemplated by the invention can take anyof a wide variety of topical dosage forms that may be prepared byconventional means. The compositions can be either solid or liquid.Solid form preparations include powders and suppositories. Suitablesolid carriers are gelatin, low melting wax, cocoa butter, and the like.

Liquid form preparations include aqueous or non-aqueous solutions,suspensions, and emulsions. As an example may be mentionedwater-propylene glycol solutions. Liquid preparations can also beformulated in solution in aqueous polyethylene glycol solution. Aqueoussolutions can be prepared by dissolving the active component in waterand adding suitable colorants, flavors, stabilizing, and thickeningagents as desired. Aqueous solutions or suspensions suitable for topicaluse can be made by dissolving or dispersing the active component inwater. The preparation may be non-aqueous, containing a penetrationenhancer such as Azone (1-dodecyl-aza-cycloheptane-2-one) or dimethylsulfoxide (DMSO) that serves to transport chemical through cellularmembranes. The preparation may contain viscous material, e.g., naturalor synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other thickening or suspending agents.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, a solution, ointment, or powder in a vial,ampoule, or other container.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted according to the particular application.

In therapeutic use as a lesion-inhibiting agent, the compositions in onepreferred embodiment are constituted in aqueous form, preferably as aconcentrated or saturated aqueous solution of the antiviral platinumcoordination compound. Cisplatin, for example is soluble in water orsaline at about 2 mg./ml. Where the composition is a cream or ointment,the same is preferably aqueous, in which the water is concentrated orsaturated with respect to the content of platinum coordination compoundin the composition.

Cisplatin, suitable for purposes of the invention, is commerciallyavailable. For example, cisplatin is available under the name Platinol(R) Bristol, as a powder for constitution with water, sterile saline orother suitable vehicle. Other platinum coordination compounds describedherein are known compounds or can be prepared as described herein.

In one preferred embodiment, the composition of the invention, is asolution of cisplatin in water, preferably a saturated solution ofcisplatin. Unexpected features of the invention include the fact thatthe method utilizing a platinum coordination compound is highlyeffective with respect to remission and the further fact that, given therelative water-insolubility of platinum coordination compounds, only arelatively small quantity of the instant platinum solute is required. Inanother preferred embodiment the composition is an aqueous cream orointment containing a minor proportion of cisplatin, preferably about0.5 mg./ml. Administration is accomplished by applying the compositionin suitable form such as a liquid, cream or ointment directly onto thesurface of the lesion in an amount sufficient to cover the surface.Preferably application is made once or twice daily. For the treatment offacial cold sores, for example, two or three applications of thesaturated aqueous solution, if early enough in the course of infection,are ordinarily sufficient to prevent the normal course of the infection.The normal course lasts from about 4 to 6 days and is characterized byincreasing sensitivity followed by blisters or lesions, then a crust andscab with final sluffing of the scab. If applied early enough, noblister develops and hence no scab. An unexpected feature of the methodis that in a substantial number of cases remission from oral skinlesions is maintained by the original treatment regimen for extendedperiods lasting in some cases up to a year or more. If the compositionis not applied at the first symptom but later, then typically the normalcourse of the infection follows, with much less severity than if nottreated, fewer blisters, smaller blisters and a smaller scab.

The preparation of cisplatin derivatives of formula cis-[Pt(NH₃)₂ P_(x)Cl_(y) ]Cl_(z) contemplated by the invention is exemplified by thepreparation of the cyclaradine derivative, as follows:

A 1-mmol amount of cisplatin is mixed with 2-mmol of cyclaradine in 100ml of water heated to 50 degrees C. with constant stirring. The solutionis heated in this manner for 5 hours. The heat source is then removedand the solution is stirred for an additional 24 hours and thenfiltered. The filtrate is rotary evaporated under low heat (40 degreesC.) to low volume (10 ml) and stored in a refrigerator overnight toprecipitate any unwanted side products. The 10 ml portion is then rotaryevaporated to dryness, treated with approximately l ml of acetone, andfiltered. The off-white product is recrystallized by dissolving in aminimum amount of water and adding acetone. The product, cis-[Pt(NH₃)₂(cyclaradine)₂ ]Cl₂,is collected by filtration and dried in vacuo overDrierite; yield, 75% of theory.

By replacing cyclaradine in this procedure with a half-equivalent or anequivalent amount of each of the other antiviral compounds named insub-group (b), one obtains the respective derivatives of that subgroup.

Having thus described our invention, the embodiments in which anexclusive property or privilege is claimed are defined as follows:
 1. Amethod of inhibiting herpetic lesions in a warm blooded animalcomprising:applying to the surface of the lesions of said warm bloodedanimal a herpes virus inhibiting amount of platinum coordinationcompound contained in a pharmaceutical composition in topical dosageform, the platinum coordination compound content being selected from thegroup of compounds consisting of cisplatin derivatives having theformula

    cis[Pt(NH.sub.3).sub.2 P.sub.x Cl.sub.y ]Cl.sub.z

where x is one or two, y and z being one when x is one and being zeroand two when x is two, and P is cyclaradine.
 2. A method according toclaim 1, where the composition contains cis-[PtNH₃)₂ cyclaradine Cl]Cl.3. A method according to claim 1 where the composition is an aqueouscomposition.
 4. A method according to claim 1 where the compositioncontains cis-[PT(NH₃)₂ (cyclaradine)₂ ]Cl₂.
 5. A method of inhibitingherpetic lesions in a warm blooded animal comprising:applying to thesurface of the lesions a herpes virus inhibiting amount of cis-[Pt(NH₃)₂(cyclaradine)₂ ]Cl₂ contained in a pharmaceutical composition in topicaldosage form.